The general purpose of this study is to determine the etiology of the contractile dysfunction that develops with hypertrophy and failure of mammalian working myocardium and to use this knowledge as a rational basis for designing specific therapeutic and preventative interventions. We plan to test the hypothesis that different stimuli to hypertrophy produce distinct alterations in cardiac excitation-contraction coupling and intracellular Ca++ handling, with a new model we have developed for recording ventricular function simultaneously with intracellular Ca++ in the left ventricles of isolated and coronary perfused hearts. Experiments will be performed in ferret models of left ventricular hypertrophy and/or failure induced by pressure-overload, volume-overload or thyroxine treatment. Recordings will be made of the mechanical and electrocardiographic activity, and intracellular Ca++ levels and transients, in hearts from hypertrophied animals and their age-matched controls. Particular attention will be directed towards identifying mechanical abnormalities that correlate with a) alterations in cytoplasmic Ca++ handling, b) changes in the Ca++ responsiveness of the contractile apparatus, and c) cellular and extracellular structural changes. We will evaluate the functional significance of the changes that we identify by comparing the systolic and diastolic responses of control vs. hypertrophied muscles to common physiologic and pathophysiologic conditions including tachycardia, stretch, hypoxia and ischemia. Particular attention will be given to evaluating whether the level of systolic and/or diastolic dysfunction can be directly correlated with the degree of hypertrophy that is present. We will use interventions with known subcellular actions to determine the etiology of the abnormalities identified in hypertrophied and failing muscle. Particular attention will be given to identifying agents that may have clinical utility in the management of patients with hypertrophy and cardiac dysfunction. These studies should increase our understanding of the functional significance of the subcellular changes that occur with three major etiologies of hypertrophy, and help to further define the role of Ca++ in the development of the hypertrophic response.